Safety and Effectiveness of Inhaling Different Dosage Recombinant Human Interferon α1B for Bronchiolitis in Children: a Systematic Review and Meta-Analysis

Purpose To systematically evaluate the safety and effectiveness of different dosages of recombinant human interferon α1b (IFNα1b) inhaled for bronchiolitis in children. Methods 7 databases, including PubMed, EMBASE, Cochrane Library, Web of Science, CNKI, Wanfang Database, and VIP, were searched. The search time was from their inception dates to March 28, 2022. A randomized controlled trial (RCT) of 2 μg/kg IFNα1b (low dosage group) monotherapy or in combination with other drugs vs. 4 μg/kg IFNα1b (high dosage group) monotherapy or in combination with the other drugs was included. The risk of bias 2.0 evaluated the RCT's quality, and the grading of recommendations assessment, development and evaluation (GRADE) tool was used for evaluating the overall quality of the evidence. Then, a meta-analysis was performed by RevMan 5.4. Results A total of 13 RCTs with 1719 children were included. The meta-analysis results showed that the high dosage group was significantly shorter than the low dosage group of the duration of hospital stays (MD = −0.40, 95%CI (−0.73, −0.07), P = 0.02) (low quality), three depressions sign disappearing time (MD = −0.60, 95%CI (−1.05, −0.14), P = 0.010) (low quality), and wheeze disappearing time (MD = −0.62, 95%CI (−1.17, −0.06),  = 0.03) (low quality). There was no significant difference between the two groups in coughing disappearing time, pulmonary rales disappearing time, wheezing sound disappearing time, or adverse event rates. Conclusions Compared with low dosage IFNα1b, high dosage IFNα1b reduces the duration of hospital stays, the disappearance time of the three depression signs, and the disappearance time of wheeze in the treatment of bronchiolitis in children. Limited by the low quality of the evidence, the conclusions still need to be supported by high-quality studies.


Introduction
Bronchiolitis is a lower respiratory tract disease that mainly occurs in children under 24 months. e peak age of onset ranges from 2 months to 6 months. e incidence of infants in the first year after birth is approximately 11%, and bronchiolitis is one of the leading causes of illness and hospitalization in children under one year old [1,2]. e most common etiology of bronchiolitis is respiratory syncytial virus (RSV) infection. Other viruses include the parainfluenza virus, influenza virus, and rhinovirus [2,3]. Unfortunately, a causative treatment of acute viral bronchiolitis does not exist due to its special pathophysiology [4,5]. In clinical practice, oxygen and fluid supplementation are usually used for symptomatic treatment [6].
Interferon (IFN) plays an essential role during bronchiolitis, particularly for children infected with RSV [7]. IFNs are a group of signaling proteins synthesized and released by host cells in response to pathogens. Normally, virus-infected cells release IFNs to enable surrounding cells to improve their anti-viral defenses [8]. is early response can influence the clinical course of RSV bronchiolitis, thereby affecting the duration of the disease and damage to the lungs [9]. However, it has been considered that common respiratory viruses, including RSV, may disrupt the host antiviral IFN response [9][10][11][12]. Based on the importance of IFN in bronchiolitis, many researchers in China have used exogenous IFN as a supplementary treatment for bronchiolitis.
Recombinant human interferon α1B (IFNα1B), as a major antiviral subtype in the Chinese population, has attracted the attention of Chinese researchers [5]. As the lesion site of bronchiolitis is located in the bronchioles, administration by nebulized has the advantages of rapidonset, fewer adverse reactions, and high compliance [5]. erefore, aerosol inhalation IFNα1B for bronchiolitis in children has been recommended by the Chinese National Formulary [13] and the Standardized Management Guidelines for Children's Nebulization Center [14]. At present, the guidelines or expert consensus recommended dosage of nebulized IFNα1b for bronchiolitis in children is 2-4 μg/kg [15,16]. However, there is still controversy about 2 μg/kg or 4 μg/kg in clinical practice. Some researchers believe that 4 μg/kg of IFNα1b has better efficacy [17,18]. Others believe that 2 μg/kg and 4 μg/kg of IFNα1b have equivalent efficacy. Considering the safety and economic effects, 2 μg/kg IFNα1b should be promoted [19,20]. erefore, this study aims to evaluate the safety and effectiveness of inhaling 2 μg/kg and 4 μg/kg of IFNα1b for bronchiolitis in children, providing evidence-based evidence for clinical practice.

Methods
is review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [21].

Search Strategy.
A total of 7 databases, including PubMed, Embase (Ovid), Cochrane Library (Ovid), Web of Science, CNKI, Wanfang Database, and VIP, were searched. Additionally, we used a manual search strategy to retrieve the relevant articles cited by the retrieved publications. e search time was from their inception dates to March 28, 2022. Medical subject headings combined with free text terms were used to search for eligible articles. Two clinical trial registration sites, including clinicaltrials.gov (https:// clinicaltrials.gov/) and the WHO International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/ trialsearch/), were searched for unpublished but eligible articles.

e Inclusion Criteria
Population: infants under 2 years old and hospitalized with a diagnosis of bronchiolitis.
Intervention/control: the high dosage group was given 4 μg/kg IFNα1b, and the low dosage group was given 2 μg/kg IFNα1b, and both were treated with nebulization. IFNα1b monotherapy or in combination with other drugs (e.g., budesonide, albuterol, and hypertonic saline) were included.
Outcomes: the primary outcome is the duration of hospital stays. e secondary outcome is based on the main clinical symptoms described in the "Expert consensus on the diagnosis, treatment and prevention of bronchiolitis (2014)," including cough disappearance time, pulmonary rales disappearance time, wheeze disappearance time, and wheezing sound disappearance time, three depression sign disappearance times, and adverse event rates.

Data Extraction and Risk-of-Bias
Assessments. Two researchers selected the included RCTs back-to-back according to the inclusion and exclusion criteria and extracted the data. Cochrane risk of bias assessment tool (ROB 2.0) was used to evaluate the RCT's quality, and the grading of recommendations assessment, development and evaluation (GRADE) tool was used to evaluate the overall quality of evidence. When two researchers had opposite opinions, disputes were decided by the third researcher. e content of the literature extraction includes basic information about the literature (such as first author and year of publication); basic information about the child (such as age and course of the disease); basic information about intervention (such as course of treatment, frequency of administration, and combined therapy); and research results (data of outcomes).

Statistical
Analysis. RevMan 5.4 statistical software provided by the Cochrane Collaboration Network was performed for meta-analysis. Relative risk (RR) and risk difference (RD) were used for dichotomous data, mean difference (MD) was used for continuous data, and 95% CIs were calculated using the Mantel-Haenszel method and the inverse variance statistical method, respectively. Heterogeneity was tested by χ 2 test and I 2 statistics, and the random effect model was performed for meta-analysis. Subgroup analysis was performed by monotherapy or combined therapy. Sensitivity analysis was performed by eliminating included RCTs one by one in each outcome.

Characteristics of the Included Studies.
e basic information of the included RCT is presented in Table 1. Among the included RCTs, 5 RCTs adopted a random number table for randomization [17,24,[26][27][28], 1 RCT adopted the envelope method for randomization [18], and the rest did not describe the method or used the wrong method. 1 RCT adopted a central randomization system for concealed allocation [17], and the rest did not mention the method for concealed allocation. Only 1 RCT risk-of-bias assessment result was "Some concerns" [17], and the results of the other RCTs were "High risk" (Figures 2 and 3); GRADE results were "low" and "very low" ( Table 2).
Chen 2018 [18] subdivided the drug administration into the early high dosage group, the early low dosage group, the late high dosage group, and the late low dosage group. Since there were no overlap children between early and late, the early and late were independently analyzed. Additionally, Zhao 2018 [17] subdivided the low dosage group into the qid group and the tid group. Since there were no overlap children between the qid group and the tid group, the qid group and the tid group were combined into the low dosage group.

Adverse Event Rates.
e results of subgroup analysis showed that regardless of IFNα1b combined therapy or monotherapy, there was no statistically significant difference in adverse event rates between the two groups ( Figures 13  and 14).

Summary.
Bronchiolitis is a lower respiratory tract infection mainly involving small airways (bronchioles). It is a common cause of illness and hospitalization in infants and young children. Severe bronchiolitis may also increase the risk of children developing asthma and continue to adulthood [6,31,32]. erefore, the etiological treatment of bronchiolitis is of great importance.
is study included 13 RCTs with 1719 children to study the safety and effectiveness of different dosages of IFNα1b inhalation for bronchiolitis. e results showed that in the duration of hospital stays, wheeze disappearing time, and three depressions sign disappearing time, the high-dosage group is significantly shorter than the low-dosage group (P ≤ 0.05), but there was no difference between the two groups in cough disappearance time, pulmonary rales disappearing time, wheezing sound disappearing time, and adverse event rates (P > 0.05).   Evidence-Based Complementary and Alternative Medicine

Comparison with Similar Research. Chen Can [33]
conducted a meta-analysis on the effectiveness and safety of IFNα1b nebulized inhalation for bronchiolitis based on 24 RCTs. e study results concluded that IFNα1b nebulized inhalation is safe and effective for bronchiolitis. However, there are still some problems in this study. e first is the high heterogeneity, such as the outcome of the duration of hospital stays (P＜0.01, I 2 � 98%), and the subgroup analysis of different doses of IFNα1b did not reduce the heterogeneity. In addition, only 3 RCTs compared different dosages of IFNα1b [17,19,30], and different dosages of IFNα1b were not further studied.

Sensitivity Analysis.
When eliminating Li 2019 [18], the heterogeneity of each outcome has decreased, and the metaanalysis results of wheeze disappearance time have changed. e possible reason is that the disease course of children in this RCT (both groups are ＜24 hours) is significantly shorter than in other RCTs (1-6 days). Another cause may be that the children have a high proportion of fever. e proportion of children with a temperature ≥39°C in the high and low dosage groups is 30% and 43%, respectively. However, the consensus points out that the temperature of children with bronchiolitis generally does not exceed 39°C [3]. When eliminating Zhao (2018), the meta-analysis results    of pulmonary rales disappearing time have changed. e possible reason is that Zhao (2018) [25] subdivides the low dosage group into three times a day and two times a day. However, it is unified into the low dosage group for statistical analysis in this study, which may lead to a change in baseline comparability. e difference in sample size between the high dosage group and the low dosage group may also be one of the reasons.

Subgroup Analysis.
Subgroup analysis showed no significant difference between the high dosage group and the low dosage group in the duration of hospital stays and adverse event rates when IFNα1b was treated with monotherapy. In terms of the duration of hospital stays, the conclusions of monotherapy and when combined with other drugs are inconsistent. However, considering that there is only 1 RCT on monotherapy, it cannot be concluded that there is no statistically significant difference in the duration of hospital stays between the high dosage group and the low dosage group when IFNα1b was treated with monotherapy. A large sample, multicenter clinical research is needed to support these results.

Risk-of-Bias Assessments.
e areas of lower quality are "Randomization process" and "Randomization process," 53.85% of the RCTs did not use or used the wrong method for randomization, such as according to the order of admission, which may lead to incomparable baselines between the two groups. In addition, 92.31% of the RCTs did not use blinding or concealed allocation, which may lead to bias when giving interventions or measuring outcome data.

Advantage.
ere has been controversy about the different dosages of IFNα1b inhaling for bronchiolitis in clinical practice. However, there is not any evidence-based medical evidence. is study uses systematic reviews and meta-analysis methods to provide a reference for clinical practice.

Limitation.
ere are some limitations to this study. First, the quality of the included RCTs is low. Only 1 RCT has a result of "Some concerns," and the others are "High risk." Second, most of the outcomes of this study adopt the disappearance time of disease symptoms, and the judgment criteria are subjective.
ird, since none of the included RCTs mentioned the symptom classification of bronchiolitis, the disease severity was not considered in this study.

Conclusions
Compared with the low dosage IFNα1b, the high dosage IFNα1b reduces the duration of hospital stays, the disappearance time of the three depression signs, and the disappearance time of wheeze in the treatment of bronchiolitis in children. Limited by the quality of the included RCTs, the above conclusions still need to be supported by large samples and high-quality studies.

Data Availability
e RevMan data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest
e author reports no conflicts of interest in this work.